Use of anti-sclerostin antibodies in the treatment of osteogenesis imperfecta

ABSTRACT

Disclosed are methods for treating a patient suffering from osteogenesis imperfecta comprising administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. Methods for increasing bone formation and reducing bone resorption in an osteogenesis imperfecta patient by administering to the patient a therapeutically effective amount of an anti-sclerostin antibody are also disclosed. Further disclosed are compositions for increasing bone formation and reducing bone resorption in an osteogenesis imperfecta patient. The compositions comprise a therapeutically effective amount of an anti-sclerostin antibody. The invention also provides an anti-sclerostin antibody for use in the treatment of osteogenesis imperfecta.

FIELD OF INVENTION

This invention relates to antibodies and their use as pharmaceuticalcompositions, more specifically to the use of anti-sclerostin antibodiesin the treatment of osteogenesis imperfecta.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Dec. 21, 2016, isnamed P069493US_SeqListing.txt and is 153 kilobytes in size.

BACKGROUND

Osteogenesis imperfecta (OI) is a rare genetic disorder of theconnective tissue characterized by bone fragility and reduced bone mass.OI comprises a group of inherited disorders which primarily, but notalways, arise from mutations in the genes encoding type I collagen.About 85% of the cases are linked to mutations in one of the two genesencoding type I collagen (COL1A1 and COL1A2). Clinically, OI ischaracterized by fragile bones that fracture easily and without anytrauma. In addition, patients with OI are often affected by muscleweakness, hearing loss, fatigue, joint laxity, curved bones, scoliosis,blue sclerae, dentinogenesis imperfecta, and short stature.

The clinical classification system divides OI into types I-V. Type I OIpatients usually suffer from a mild non-deforming disease that is oftenassociated with a premature stop codon in COL1A1. This defect results ina reduced rate of type I collagen production and quantitatively lesscollagen in bone. Patients with type II OI usually die during theperinatal period, as a result of respiratory failure from multiplesevere fractures that include the rib cage. Types III and IV OI areoften associated with glycine substitution in COL1A1 and COL1A2, whichis a qualitative defect that prevents the 3 polypeptide chains of type Icollagen to intertwine properly to form a normal triple alpha helicalstructure. Type III OI is the most severe form of OI in those affectedchildren who survive infancy, whereas patients with type IV have mild tomoderate bone deformities. Type V is infrequent.

There remains a need for therapeutic methods and agents for thetreatment of OI.

BRIEF SUMMARY OF THE INVENTION

The inventors surprisingly found that human patients with osteogenesisimperfecta (OI) can successfully be treated with an anti-sclerostinantibody, as established by the examples, which confirm that theanti-sclerostin antibody BPS804 can both increase bone formation andreduce bone resorption in patients with OI. We disclosed high affinity,neutralizing, fully human anti-sclerostin monoclonal antibodies(collectively “the human anti-sclerostin monoclonal antibody”) and theirpotent in vitro activity and in vivo activity in our U.S. Pat. Nos.7,879,322, 8,246,953, and 8,486,661, which are hereby incorporated intheir entirety by reference thereto.

In one aspect, the present invention is a method for treatingosteogenesis imperfecta (OI) in a human patient comprising administeringto the human patient a therapeutically effective amount of ananti-sclerostin antibody comprising (a) a heavy chain variable regionCDR1 comprising an amino acid sequence set forth in SEQ ID NO:4; (b) aheavy chain variable region CDR2 comprising an amino acid sequence setforth in SEQ ID NO:15; (c) a heavy chain variable region CDR3 comprisingan amino acid sequence set forth in SEQ ID NO:26; (d) a light chainvariable region CDR1 comprising an amino acid sequence set forth in SEQID NO:37; (e) a light chain variable region CDR2 comprising an aminoacid sequence set forth in SEQ ID NO:48; and (f) a light chain variableregion CDR3 comprising an amino acid sequence set forth in SEQ ID NO:59.This anti-sclerostin antibody is also referred to herein as ‘theantibody of the invention’ The anti-sclerostin antibody of the inventionis administered intravenously at a dose of 1-50 mg per kg body weight ofthe human patient.

In one embodiment, the present invention is a method for increasing boneformation and reducing bone resorption in an osteogenesis imperfectapatient by administering to the patient a therapeutically effectiveamount of the anti-sclerostin antibody of the invention. In anotheraspect, the invention provides an anti-sclerostin antibody of theinvention, for use in the treatment of osteogenesis imperfecta. In oneembodiment the anti-sclerostin antibody increases bone formation and/orreduces bone resorption.

In another embodiment, the anti-sclerostin antibody comprises animmunoglobulin heavy chain variable domain (VH) having at least 90 (suchas at least 95, 98, or 99 or 100) percent identity to the amino acidsequence set forth in SEQ ID NO: 70. In yet another embodiment, theanti-sclerostin antibody comprises an immunoglobulin light chainvariable domain (VL) having at least 90 (such as at least 95, 98, or 99or 100) percent identity to the amino acid sequence set forth in SEQ IDNO: 81. In still another embodiment, the anti-sclerostin antibodycomprises a VH having at least 90 (such as at least 95, 98, or 99 or100) percent identity to the amino acid sequence set forth in SEQ ID NO:70, and a VL having at least 90 (such as at least 95, 98, or 99 or 100)percent identity to the amino acid sequence set forth in SEQ ID NO: 81.In yet another embodiment, the anti-sclerostin antibody comprises a VHhaving the amino acid sequence set forth in SEQ ID NO: 70, and a VLhaving the amino acid sequence set forth in SEQ ID NO: 81. In yet stillanother embodiment, the anti-sclerostin antibody comprises a heavy chainhaving at least 90 (such as at least 95, 98, or 99 or 100) percentidentity to the amino acid sequence set forth in SEQ ID NO: 114 or 172,and/or at least 90 (such as at least 95, 98, or 99 or 100) percentidentity to a light chain having the amino acid sequence set forth inSEQ ID NO: 125 or 173. In one embodiment, the anti-sclerostin antibodycomprises a heavy chain having the amino acid sequence set forth in SEQID NO: 172 and a light chain having the amino acid sequence set forth inSEQ ID NO: 173.

In some embodiments, the therapeutically effective amount of theanti-sclerostin antibody of the invention is about 1-50 mg of saidantibody per kg body weight of the human patient.

Another aspect of the invention is a pharmaceutical composition forincreasing bone formation and reducing bone resorption in anosteogenesis imperfecta patient. In some embodiments, the compositioncontains an anti-sclerostin antibody comprising: a) at least oneimmunoglobulin heavy chain variable domain (VH) which comprises insequence hypervariable regions a heavy chain variable region CDR1, aheavy chain variable region CDR2, and a heavy chain variable regionCDR3, said heavy chain variable region CDR1 comprising an amino acidsequence set forth in SEQ ID NO: 4, said heavy chain variable regionCDR2 comprising an amino acid sequence set forth in SEQ ID NO: 15, andsaid heavy chain variable region CDR3 comprising an amino acid sequenceset forth in SEQ ID NO: 26; and b) at least one immunoglobulin lightchain variable domain (VL) which comprises in sequence hypervariableregions a light chain variable region CDR1, a light chain variableregion CDR2, and a light chain variable region CDR3, said light chainvariable region CDR1 comprising an amino acid sequence set forth in SEQID NO: 37, said light chain variable region CDR2 comprising an aminoacid sequence set forth in SEQ ID NO: 48, and said light chain variableregion CDR3 comprising an amino acid sequence set forth in SEQ ID NO:59.

In another embodiment, the anti-sclerostin antibody in thepharmaceutical composition comprises a VH having at least 95 percentidentity to the amino acid sequence set forth in SEQ ID NO: 70. In yetanother embodiment, the anti-sclerostin antibody comprises a VL havingat least 95 percent identity to the amino acid sequence set forth in SEQID NO: 81.

In still another embodiment, the anti-sclerostin antibody comprises a VHhaving at least 95 percent identity to the amino acid sequence set forthin SEQ ID NO: 70, and a VL having at least 95 percent identity to theamino acid sequence set forth in SEQ ID NO: 81. In yet anotherembodiment, the anti-sclerostin antibody comprises a VH having the aminoacid sequence set forth in SEQ ID NO: 70, and a VL having the amino acidsequence set forth in SEQ ID NO: 81. In yet still another embodiment,the anti-sclerostin antibody comprises a heavy chain having the aminoacid sequence set forth in SEQ ID NO: 114 or 172, and/or a light chainhaving the amino acid sequence set forth in SEQ ID NO: 125 or 173.

In one aspect the invention provides a pharmaceutical compositioncomprising an anti-sclerostin antibody as disclosed herein. In oneembodiment the pharmaceutical composition can be used in themethods/uses described herein

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a table with results of the one-sample t-test analysisresults for the bone metabolism biomarkers.

FIG. 2 shows a table with results of the two-sample t-test analysis ofthe bone metabolism biomarkers.

FIG. 3 shows a graph depicting ratios to baseline in geometric means(plus or minus SD) for PINP.

FIG. 4 shows a graph depicting ratios to baseline in geometric means(plus or minus SD) for PICP.

FIG. 5 shows a graph depicting ratios to baseline in geometric means(plus or minus SD) for BSAP.

FIG. 6 shows a graph depicting ratios to baseline in geometric means(plus or minus SD) for OC.

FIG. 7 shows a graph depicting Bayesian posterior probabilities ofratios to baseline for BMD of lumbar spine (measured by DXA) data.

FIG. 8 shows a graph depicting ratios of baseline in geometric means(plus or minus SD) for CTX-1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the unexpected and surprising findingsthat human patients with osteogenesis imperfecta (OI) can successfullybe treated with an anti-sclerostin antibody. Administration of ananti-sclerostin antibody to human OI patients increases bone formationand reduces bone resorption, as shown in the examples.

By way of background, sclerostin is a naturally occurring protein thatin humans is encoded by the SOST gene. Sclerostin is a secretedglycoprotein with a C terminal cysteine knot-like (CTCK) domain andsequence similarity to the DAN (differential screening-selected geneaberrative in neuroblastoma) family of bone morphogenetic protein (BMP)antagonists.

As shown for the first time by the present inventors, inhibitingsclerostin with anti-sclerostin antibodies boosts bone formation anddensity and provides beneficial effects in treating OI in humans. Unlikeprevious anabolic treatments using GH or PTH which increase boneturnover, a treatment with an anti-sclerostin antibody offers theadvantage of stimulating bone formation while inhibiting bone resorptionin OI patients. The clinical utility of anti-sclerostin antibodiestherefore includes the treatment of osteogenesis imperfecta in humanswhere bone formation is of therapeutic benefit in a diseasecharacterized by a significant lack of bone matrix.

As such, the invention is directed to methods of using anti-sclerostinantibodies in the treatment of OI, as well as compositions comprisinganti-sclerostin antibodies for use in treating OI. In one aspect theinvention is concerned with the treatment of osteogenesis imperfectatypes I, III or IV. Accordingly, the invention provides anti-sclerostinantibodies and pharmaceutical compositions comprising said antibodiesfor use in the treatment of OI, preferably OI types I, III or IV. Theanti-sclerostin antibody of the invention is a human monoclonalanti-sclerostin antibody.

The methods and uses of the anti-sclerostin antibody in the presentinvention were unexpected and surprising because the antibody treatmentin OI patients results in both an increase of bone formation and areduction of bone resorption.

In order that the present invention may be more readily understood,certain terms are first defined. Additional definitions are set forththroughout the detailed description.

The term “comprising” encompasses “including” as well as “consisting”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional e.g. X+Y.

The term “about” in relation to a numerical value x means, for example,x±10%.

The term sclerostin refers to human sclerostin as defined in SEQ ID NO:155. Recombinant human sclerostin can be obtained from R&D Systems(Minneapolis, Minn., USA; 2006 cat#1406-ST-025). Additionally,recombinant mouse sclerostin/SOST is commercially available from R&DSystems (Minneapolis, Minn., USA; 2006 cat#1589-ST-025). U.S. Pat. Nos.6,395,511 and 6,803,453, and U.S. Patent Publications 20040009535 and20050106683 refer to anti-sclerostin antibodies in general.

The term “antibody” as referred to herein includes whole antibodies andany antigen binding fragment (i.e., “antigen-binding portion”) or singlechains thereof. A naturally occurring “antibody” is a glycoproteincomprising at least two heavy (H) chains and two light (L) chainsinter-connected by disulfide bonds. Each heavy chain is comprised of aheavy chain variable region (abbreviated herein as VH) and a heavy chainconstant region. The heavy chain constant region is comprised of threedomains, CH1, CH2 and CH3. Each light chain is comprised of a lightchain variable region (abbreviated herein as VL) and a light chainconstant region. The light chain constant region is comprised of onedomain, CL. The VH and VL regions can be further subdivided into regionsof hypervariability, termed complementarity determining regions (CDR),interspersed with regions that are more conserved, termed frameworkregions (FR). Each VH and VL is composed of three CDRs and four FRsarranged from amino-terminus to carboxy-terminus in the following order:FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavyand light chains contain a binding domain that interacts with anantigen. The constant regions of the antibodies may mediate the bindingof the immunoglobulin to host tissues or factors, including variouscells of the immune system (e.g., effector cells) and the firstcomponent (C1q) of the classical complement system. In one embodiment,reference to an antibody herein embraces isolated, monoclonal, human andhumanized monoclonal antibodies.

The term “antigen-binding portion” of an antibody (or simply “antigenportion”), as used herein, refers to full length or one or morefragments of an antibody that retain the ability to specifically bind toan antigen (e.g., sclerostin). It has been shown that theantigen-binding function of an antibody can be performed by fragments ofa full-length antibody. Examples of binding fragments encompassed withinthe term “antigen-binding portion” of an antibody include a Fabfragment, a monovalent fragment consisting of the VL, VH, CL and CH1domains; a F(ab)₂ fragment, a bivalent fragment comprising two Fabfragments linked by a disulfide bridge at the hinge region; a Fdfragment consisting of the VH and CH1 domains; a Fv fragment consistingof the VL and VH domains of a single arm of an antibody; a dAb fragment(Ward et al., 1989 Nature 341:544-546), which consists of a VH domain;and an isolated complementarity determining region (CDR).

Furthermore, although the two domains of the Fv fragment, VL and VH, arecoded for by separate genes, they can be joined, using recombinantmethods, by a synthetic linker that enables them to be made as a singleprotein chain in which the VL and VH regions pair to form monovalentmolecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci.85:5879-5883). Such single chain antibodies are also intended to beencompassed within the term “antigen-binding region” of an antibody.These antibody fragments are obtained using conventional techniquesknown to those of skill in the art, and the fragments are screened forutility in the same manner as are intact antibodies.

An “isolated antibody”, as used herein, refers to an antibody that issubstantially free of other antibodies having different antigenicspecificities (e.g., an isolated antibody that specifically bindssclerostin is substantially free of antibodies that specifically bindantigens other than sclerostin). An isolated antibody that specificallybinds sclerostin may, however, have cross-reactivity to other antigens,such as sclerostin molecules from other species. Moreover, an isolatedantibody may be substantially free of other cellular material and/orchemicals. In one embodiment, reference to an antibody herein means anisolated antibody.

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope.

The term “human antibody”, as used herein, is intended to includeantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences or antibody containing consensusframework sequences derived from human framework sequences analysis asdescribed in Knappik, et al. (2000. J Mol Biol 296, 57-86).

The human antibodies may include amino acid residues not encoded byhuman sequences (e.g., mutations introduced by random or site-specificmutagenesis in vitro or by somatic mutation in vivo). However, the term“human antibody”, as used herein, is not intended to include antibodiesin which CDR sequences derived from the germline of another mammalianspecies, such as a mouse, have been grafted onto human frameworksequences.

The term “human monoclonal antibody” refers to antibodies displaying asingle binding specificity which have variable regions in which both theframework and CDR regions are derived from human sequences. In oneembodiment, the human monoclonal antibodies are produced by a hybridomawhich includes a B cell obtained from a transgenic nonhuman animal,e.g., a transgenic mouse, having a genome comprising a human heavy chaintransgene and a light chain transgene fused to an immortalized cell.

The term “recombinant human antibody”, as used herein, includes allhuman antibodies that are prepared, expressed, created or isolated byrecombinant means, such as antibodies isolated from an animal (e.g., amouse) that is transgenic or transchromosomal for human immunoglobulingenes or a hybridoma prepared therefrom, antibodies isolated from a hostcell transformed to express the human antibody, e.g., from atransfectoma, antibodies isolated from a recombinant, combinatorialhuman antibody library, and antibodies prepared, expressed, created orisolated by any other means that involve splicing of all or a portion ofa human immunoglobulin gene, sequences to other DNA sequences. Suchrecombinant human antibodies have variable regions in which theframework and CDR regions are derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies can be subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline VH and VL sequences, may not naturally existwithin the human antibody germline repertoire in vivo.

In one embodiment, and as used herein, an antibody that binds sclerostin(e.g. an anti-sclerostin antibody) means that it specifically binds tosclerostin polypeptide. “Specifically binds to sclerostin polypeptide”is intended to refer to an antibody that binds to sclerostin polypeptidewith a K_(D) of 1×10⁻⁸ M or less, 1×10⁻⁹ M or less, or 1×10⁻¹⁰ M orless. The term “K_(D)”, as used herein, is intended to refer to thedissociation constant, which is obtained from the ratio of K_(d) toK_(a) (i.e. K_(d)/K_(a)) and is expressed as a molar concentration (M).K_(D) values for antibodies can be determined using methods wellestablished in the art. A method for determining the K_(D) of anantibody is by using surface plasmon resonance, or using a biosensorsystem such as a Biacore® system.

Standard assays to evaluate the binding ability of the antibodies towardsclerostin of various species are known in the art, including forexample, ELISAs, western blots and RIAs. Suitable assays are describedin detail in WO2009/047356. The binding kinetics (e.g., bindingaffinity) of the antibodies also can be assessed by standard assaysknown in the art, such as by Biacore analysis. Assays to evaluate theeffects of the antibodies on functional properties of sclerostin (e.g.,receptor binding, preventing or ameliorating osteolysis) are describedin further detail in WO2009/047356.

As used herein, the percent identity between two sequences is a functionof the number of identical positions shared by the sequences (i.e., %identity=# of identical positions/total # of positions×100), taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences. The comparison ofsequences and determination of percent identity between two sequencescan be accomplished using a mathematical algorithm, as described in thenon-limiting examples below.

The percent identity between two amino acid sequences can be determinedusing the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci.,4:11-17, 1988) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4. In addition, the percent identity betweentwo amino acid sequences can be determined using the Needleman andWunsch (J. Mol, Biol. 48:444-453, 1970) algorithm which has beenincorporated into the GAP program in the GCG software package (availableat http://www.gcg.com), using either a Blossom 62 matrix or a PAM250matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a lengthweight of 1, 2, 3, 4, 5, or 6.

Additionally or alternatively, the protein sequences of the presentinvention can further be used as a “query sequence” to perform a searchagainst public databases to, for example, identify related sequences.Such searches can be performed using the)(BLAST program (version 2.0) ofAltschul, et al., 1990 J. Mol. Biol. 215:403-10. BLAST protein searchescan be performed with the XBLAST program, score=50, wordlength=3 toobtain amino acid sequences homologous to the antibody molecules of theinvention. To obtain gapped alignments for comparison purposes, GappedBLAST can be utilized as described in Altschul et al., 1997 NucleicAcids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLASTprograms, the default parameters of the respective programs (e.g.,XBLAST and NBLAST) can be used. See http:www.ncbi.nhn.nih.gov.

Various aspects of the invention are described in further detail in thefollowing subsections.

Methods of Treatment with and Uses of Anti-Sclerostin Antibodies in OITreatment

In one aspect, the invention is directed to methods of treating OIpatients with anti-sclerostin antibodies as described herein or uses ofthese anti-sclerostin antibodies in OI treatment. The treatment withanti-sclerostin antibodies may both increase bone formation and reducebone resorption in the OI patients. In one aspect, the inventionprovides an anti-sclerostin antibody for use in the treatment of OI.Suitable anti-sclerostin antibodies for use in the treatment of OI aredisclosed herein.

In some embodiments, the invention is a method for increasing boneformation and reducing bone resorption in an OI patient and the methodcomprises administering to the patient a therapeutically effectiveamount of an anti-sclerostin antibody. In one embodiment, treatment ofan OI patient with an anti-sclerostin antibody of the inventionincreases bone formation and/or reduces bone resorption in said OIpatient.

The anti-sclerostin antibody of the invention comprises: a heavy chainvariable region CDR1 of SEQ ID NO: 4; a heavy chain variable region CDR2of SEQ ID NO: 15; a heavy chain variable region CDR3 of SEQ ID NO: 26; alight chain variable region CDR1 of SEQ ID NO: 37; a light chainvariable region CDR2 of SEQ ID NO: 48; and a light chain variable regionCDR3 of SEQ ID NO: 59. In one embodiment, the CDR regions are delineatedusing the Kabat system (Kabat, E. A., et al., 1991 Sequences of Proteinsof Immunological Interest, Fifth Edition, U.S. Department of Health andHuman Services, NIH Publication No. 91-3242).

In a certain embodiment, the anti-sclerostin antibody comprises: a VHpolypeptide amino acid sequence having at least 95 percent identity tothe amino acid sequence set forth as SEQ ID NO: 70.

In a certain embodiment, the anti-sclerostin antibody comprises: a VLpolypeptide amino acid sequence having at least 95 percent identity tothe amino acid sequence set forth as SEQ ID NO: 81.

In a certain embodiment, the anti-sclerostin antibody comprises: a VHpolypeptide amino acid sequence having at least 95 percent identity tothe amino acid sequence set forth as SEQ ID NO: 70 and a VL polypeptideamino acid sequence having at least 95 percent identity to the aminoacid sequence set forth as SEQ ID NO: 81.

In a certain embodiment, the anti-sclerostin antibody comprises: the VHpolypeptide amino acid sequence set forth as SEQ ID NO: 70 and the VLpolypeptide amino acid sequence set forth as SEQ ID NO: 81.

In a certain embodiment, the anti-sclerostin antibody comprises: theheavy chain polypeptide amino acid sequence set forth as SEQ ID NO: 114or 172 and the light chain polypeptide amino acid sequence set forth asSEQ ID NO: 125 or 173.

In a preferred embodiment, the anti-sclerostin antibody is the antibodyBPS804, which is a human anti-sclerostin monoclonal antibody. BPS804comprises the following CDRs: heavy chain variable region CDR1 of SEQ IDNO: 4; heavy chain variable region CDR2 of SEQ ID NO: 15; heavy chainvariable region CDR3 of SEQ ID NO: 26; light chain variable region CDR1of SEQ ID NO: 37; light chain variable region CDR2 of SEQ ID NO: 48; andlight chain variable region CDR3 of SEQ ID NO: 59. The VH and VLsequences of BPS804 comprise: the VH polypeptide amino acid sequence setforth as SEQ ID NO: 70 and the VL polypeptide amino acid sequence setforth as SEQ ID NO: 81. The heavy and light chain sequences of BPS804comprise: the heavy chain polypeptide amino acid sequence set forth asSEQ ID NO: 172 and the light chain polypeptide amino acid sequence setforth as SEQ ID NO: 173.

Additional characteristics of the anti-sclerostin antibodies of thepresent invention, such as BPS804 are described in WO2009/047356, whichdisclosure, discussion and data is hereby incorporated by referencethereto. By way of example only, the antibodies of the invention mayexhibit at least one of the following functional properties: theantibody blocks the inhibitory effect of sclerostin in a cell based wntsignaling assay, the antibody blocks the inhibitory effect of sclerostinin a cell based mineralization assay, the antibody blocks the inhibitoryeffect of sclerostin in Smad1 phosphorylation assay, the antibodyinhibits binding of sclerostin to the LRP-6, and the antibody increasesbone formation and mass and density. As noted above, these propertiesare described in detail in WO2009/047356.

In relation to an antibody that “blocks the inhibitory effect ofsclerostin in a cell based wnt signaling assay”, this is intended torefer to an antibody that restores wnt induced signaling in the presenceof sclerostin in a cell-based super top flash (STF) assay with an IC50less than 1 mM, 100 nM, 20 nM, 10 nM or less. WO2009/047356 describessaid wnt STF assay.

In relation to an antibody that “blocks the inhibitory effect ofsclerostin in a cell based mineralization assay”, this is intended torefer to an antibody that restores BMP2 induced mineralisation in thepresence of sclerostin in a cell-based assay with an IC50 less than 1mM, 500 nM, 100 nM, 10 nM, 1 nM or less.

In relation to an antibody that “blocks the inhibitory effect ofsclerostin in Smad1 phosphorylation assay”, this is intended to refer toan antibody that restores BMP6 induced Smad1 phosphorylation in thepresence of sclerostin in a cell based assay with an IC50 less than 1mM, 500 nM, 100 nM, 10 nM, 1 nM or less.

In relation to an antibody that “inhibits binding of sclerostin to theLRP-6”, this is intended to refer to an antibody that inhibitssclerostin binding to LRP-6 with a IC50 of 1 mM, 500 nM, 100 nM, 10 nM,5 nM, 3 nM, 1 nM or less.

In relation to an antibody that “increases bone formation and mass anddensity”, this is intended to refer to an antibody that is capable ofreaching bone formation, mass and density at the level of dailyintermittent treatment with high anabolic dose of PTH, such as a dailyintermittent treatment with 100 μg/kg of hPTH.

In one embodiment, the anti-sclerostin antibody of the inventionincreases bone formation and/or reduces bone resorption.

Dosage Regimen

Dosage regimens are adjusted to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for thesubjects to be treated; each unit contains a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of sensitivity in individuals. In one embodiment, the dosageunit form of the invention comprises 10-5000 mg of anti-sclerostinantibody, or 10-4000 mg, 10-3000 mg, 10-2000 mg, 10-1000 mg, 10-500 mg,10-400 mg, 10-300 mg, 10-200 mg, 10-150 mg, 10-100 mg, 10-80 mg, 10-60mg, 10-50 mg, 10-40 mg, 10-35 mg, 10-30 mg, 10-25 mg, 10-20 mg, or 10-15mg. In one embodiment, the dosage unit form comprises 150 mg ofanti-sclerostin antibody.

In one embodiment, the anti-sclerostin antibody of the dosage unit formis in a lyophilized state which may be in powder form. In anotherembodiment, the anti-sclerostin antibody of the dosage unit form is insolution. In one embodiment the dosage unit form of the invention iscontained within a container such as a vial. In another embodiment, thecontainer is a syringe.

In addition to the active substance (i.e. the anti-sclerostin antibody),the dosage unit form may comprise one or more additional substancesand/or excipients. In one embodiment, the dosage unit form comprises oneor more of the following: sucrose, arginine hydrochloride, L-histidine,polysorbate 80, hydrochloric acid and water for injection (wfi).

In one aspect, the invention provides a kit comprising ananti-sclerostin antibody of the invention or a pharmaceuticalcomposition of the invention, or a lyophilizate of the invention, or adosage unit form of the invention. Optionally the kit may furthercomprise instructions in the form of e.g. a patient information leaflet,instructions for reconstitution of the lyophilizate, and/oradministration instructions. In one embodiment, the kit includes asyringe comprising one or more therapeutically effective doses of theanti-sclerostin antibody. The anti-sclerostin antibody in the syringecan be present in liquid or lyophilized form. The kit may furthercomprise a solution for reconstitution of the lyophilizate, and/or aninfusion solution (e.g. dextrose 5% in sterile water).

For administration of the anti-sclerostin antibody, the dosage rangesfrom about 1 milligram of said antibody per kilogram body weight of thepatient (herein referred to as “mg/kg” throughout this application) to50 mg/kg, more usually about 1 to 30 mg/kg, and still more usually about1 to 20 mg/kg. For example dosages can be about 5 mg/kg body weight,about 10 mg/kg body weight, about 20 mg/kg body weight, or within therange of about 5-20 mg/kg.

In another aspect of the invention, the anti-sclerostin antibody isadministered at a dose of 1-50 mg per kg body weight of a patient, suchas at 2-50, 3-50, 5-50, 8-50 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 2-50 mg per kg body weight of a patient, such as at 2-45, 2-40,2-35, 2-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 3-50 mg per kg body weight of a patient, such as at 3-45, 3-40,3-35, 3-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 5-50 mg per kg body weight of a patient, such as at 5-45, 5-40,5-35, 5-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 8-50 mg per kg body weight of a patient, such as at 8-45, 8-40,8-35, 8-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 10-50 mg per kg body weight of a patient, such as at 10-45,10-40, 10-35, 10-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 11-50 mg per kg body weight of a patient, such as at 11-45,11-40, 11-35, 11-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 12-50 mg per kg body weight of a patient, such as at 12-45,12-40, 12-35, 12-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 15-50 mg per kg body weight of a patient, such as at 15-45,15-40, 15-35, 15-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 18-50 mg per kg body weight of a patient, such as at 18-45,18-40, 18-35, 18-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 20-50 mg per kg body weight of a patient, such as at 20-45,20-40, 20-35, 20-30 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 5-20 mg per kg body weight of a patient, such as at 8-20, 10-20,12-20, 15-20 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 10 mg per kg body weight of a patient, or at 1, 2, 3, 4, 5, 6,7, 8, 9 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 20 mg per kg body weight of a patient, or at 11, 12, 13, 14, 15,17, 18, 19 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 30 mg per kg body weight of a patient, or at 21, 22, 23, 24, 25,26, 27, 28, 29 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of 10 mg per kg body weight of a patient. In a related embodiment,the anti-sclerostin antibody is administered at a dose of 8-12 mg/kg, orat 8-15 mg/kg.

In one embodiment, the anti-sclerostin antibody is administered at adose of or 20 mg per kg body weight of a patient. In a relatedembodiment, the anti-sclerostin antibody is administered at a dose of18-22 mg/kg, or at 15-25 mg/kg.

In another aspect of the invention, the anti-sclerostin antibody isadministered at a dose of 10-5000 mg. In one embodiment, theanti-sclerostin antibody is administered at a dose of 10-4000 mg,10-3000 mg, 10-2000 mg, 10-1000 mg, 10-500 mg, 10-400 mg, 10-300 mg,10-200 mg, 10-150 mg, 10-100 mg, 10-80 mg, 10-60 mg, 10-50 mg, 10-40 mg,10-35 mg, 10-30 mg, 10-25 mg, 10-20 mg, or 10-15 mg. In one embodiment,the anti-sclerostin antibody is administered at a dose of 10-3500 mg. Inone embodiment, the anti-sclerostin antibody is administered at a doseof 10-3000 mg. In one embodiment, the anti-sclerostin antibody isadministered at a dose of 10-2000 mg. In one embodiment, theanti-sclerostin antibody is administered at a dose of 10-1500 mg. In oneembodiment, the anti-sclerostin antibody is administered at a dose of10-1000 mg.

An exemplary treatment regime entails administration of multiple doses,which may be of the same dosage or different dosages ranging from, e.g.,about 5-20 mg/kg, under a dosing schedule of once per week, once everytwo weeks, once every three weeks, once every four weeks, once a monthor monthly, once every five weeks, once every six weeks, once everyseven weeks, once every eight weeks, once every two months (i.e.bi-monthly), once every three months (i.e. quarterly), once every threeto six months, semi-annually, or annually. In some embodiments, themultiple doses can be 2-20 doses, more usually 2-10 doses, and stillmore usually 3-5 doses, and still further more usually 3 doses under adosing schedule of once per week, once every two weeks, once every threeweeks, once every four weeks, once a month or monthly, once every fiveweeks, once every six weeks, once every seven weeks, once every eightweeks, once every two months (i.e. bi-monthly), once every three months,once every three to six months, semi-annually, or annually.

In another aspect of the invention, the anti-sclerostin antibody may beadministered to a patient on a daily, weekly, bi-weekly, monthly,bi-monthly, quarterly or annual basis.

In one embodiment, the anti-sclerostin antibody is administered to apatient on a weekly basis. In another embodiment, administration occursevery 2, 3, 4, 5, 6, or 7 weeks.

In one embodiment, the anti-sclerostin antibody is administered to apatient on a monthly basis. In another embodiment, administration occursevery 2, 3, 4, 5 or 6 months.

In one embodiment, the anti-sclerostin antibody is administered to apatient every three months (i.e. on a quarterly basis). In the event ofmore frequent administration regimens, such as weekly or dailyadministration, an administration route that allows patients toself-administer is preferred. By way of example, a subcutaneous, topicalor oral administration route may facilitate self-administration of theanti-sclerostin antibody and preclude visits to a doctor/hospital inorder to receive treatment.

Another exemplary treatment regime entails administration of multipledoses, which may be of the same dosage or different dosages rangingfrom, e.g., about 5-20 mg/kg, until a treatment target is achieved orreached in the patient. The treatment target is achieved or reachedafter a certain number of doses are administered. The treatment targetmay be a complete normalization of bone mineral density, a partialnormalization of bone mineral density, or a reduced frequency of bonefracture incidence, an increased level of bone formation markers, or adecreased level of bone resorption markers. Thus, in one embodiment, theinvention provides an anti-sclerostin antibody for use in the treatmentof OI, wherein the anti-sclerostin antibody reduces the fracture rate ina patient/patient population compared to a control patient/patientpopulation. Preferably, the anti-sclerostin antibody reduces thefracture rate by at least 10, 20, 30, 35, 40, 50, 60, 70, 80, or 90percent. In one embodiment the anti-sclerostin antibody reduces thefracture rate by at least 30 percent. In one embodiment, fractures aredefined as peripheral or vertebral fractures (including all major,minor, and vertebral clinical fractures; fractures only detected bymeans of investigations without clinical symptoms are not included),confirmed by radiologic investigation(s). In one embodiment the fracturerate pertains to a population of patients. The patient population andcontrol patient populations are preferably of a size that allow astatistically significant comparison to be made.

In one aspect of the invention, a treatment regimen entails a firstdosing regimen optionally followed by a second dosing regimen. A dosingregimen includes the dose administered and the frequency ofadministration. These can be selected from any of the aforementioneddoses and administration frequencies and can be varied according to theclinical requirements of a patient. The doses and administrationfrequencies disclosed above are hereby explicitly embraced in thisaspect of the invention.

By way of example, in one embodiment, the first dosing regimen is 1-50mg per kg body weight of a patient, or 2-50 mg/kg, or 3-50 mg/kg, or5-50 mg/kg, or 8-50 mg/kg, or 3-30 mg/kg, 5-30 mg/kg, or 8-30 mg/kg, or10-30 mg/kg, or 12-30 mg/kg, or 15-30 mg/kg, or 12-25 mg/kg, or 15-25mg/kg administered on a monthly basis. In another exemplary embodiment,the first dosing regimen is 10-5000 mg administered on a monthly basis.

In one embodiment, the first dosing regimen is 1-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 2-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 2-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 3-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 3-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 5-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 5-25 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 12-25 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the first dosing regimen is 20 mg per kg body weightof a patient administered on a monthly basis.

In another exemplary embodiment, the first dosing regimen is 1-50 mg perkg body weight of a patient, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50mg/kg, or 8-50 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or 12-30 mg/kg, or15-30 mg/kg, or 12-25 mg/kg, or 15-25 mg/kg administered on a quarterlybasis. In another exemplary embodiment, the first dosing regimen is10-5000 mg administered on a quarterly basis.

In one embodiment, the first dosing regimen is 2-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the first dosing regimen is 3-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the first dosing regimen is 5-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the first dosing regimen is 5-25 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the first dosing regimen is 12-25 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the first dosing regimen is 20 mg per kg body weightof a patient administered on a quarterly basis.

In one embodiment and by way of example only, the second dosing regimen1-50 mg per kg body weight of a patient, or 2-50 mg/kg, or 3-50 mg/kg,or 5-50 mg/kg, or 8-50 mg/kg, or 3-30 mg/kg, 5-30 mg/kg, or 8-30 mg/kg,or 10-30 mg/kg, or 12-30 mg/kg, or 12-25 mg/kg, or 15-30 mg/kg, or 15-25mg/kg administered on a monthly basis. In another exemplary embodiment,the second dosing regimen is 10-5000 mg administered on a monthly basis

In one embodiment, the second dosing regimen is 1-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 2-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 2-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 3-50 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 3-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 5-30 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 5-25 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 12-25 mg per kg bodyweight of a patient administered on a monthly basis.

In one embodiment, the second dosing regimen is 20 mg per kg body weightof a patient administered on a monthly basis.

In another embodiment, the second dosing regimen 1-50 mg per kg bodyweight of a patient, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50 mg/kg, or8-50 mg/kg, or 3-30 mg/kg, 5-30 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or12-30 mg/kg, or 12-25 mg/kg, or 15-30 mg/kg, or 15-25 mg/kg administeredon a bi-monthly basis. In another exemplary embodiment, the seconddosing regimen is 10-5000 mg administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 1-50 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 2-50 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 2-30 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 3-50 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 3-30 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 5-30 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 5-25 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 12-25 mg per kg bodyweight of a patient administered on a bi-monthly basis.

In one embodiment, the second dosing regimen is 20 mg per kg body weightof a patient administered on a bi-monthly basis.

In another exemplary embodiment, the second dosing regimen is 1-50 mgper kg body weight of a patient, or 2-50 mg/kg 3-50 mg/kg, or 5-50mg/kg, or 8-50 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or 12-30 mg/kg, or12-25 mg/kg, or 15-30 mg/kg, or 15-25 mg/kg administered on a quarterlybasis. In another exemplary embodiment, the second dosing regimen is10-5000 mg administered on a quarterly basis.

In one embodiment, the second dosing regimen is 2-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the second dosing regimen is 3-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the second dosing regimen is 5-30 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the second dosing regimen is 5-25 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the second dosing regimen is 12-25 mg per kg bodyweight of a patient administered on a quarterly basis.

In one embodiment, the second dosing regimen is 20 mg per kg body weightof a patient administered on a quarterly basis.

In a related embodiment, the first dosing regimen is 20 mg per kg bodyweight of a patient administered on a monthly basis and the seconddosing regimen is 20 mg per kg body weight of a patient administered ona bi-monthly or quarterly basis.

The time period of administration of the first and second dosingregimens can be varied according to the clinical requirements of apatient. Thus, the first dosing regimen is administered for a first timeperiod and the second dosing regimen is administered for a second timeperiod.

Thus, and by way of example, the first and second time periods can be 1month, 6 months, 12 months or any other time period.

In one embodiment, an anti-sclerostin antibody can be initiallyadministered to a patient on a monthly basis for a period of 1 year,followed by administration on a bi-monthly or quarterly basis for aperiod of at least 1 year (such as 2 or more years).

Thus, in one embodiment, the first dosing regimen can be 20 mg per kgbody weight of a human patient administered on a monthly basis for aperiod of 1 year, and the second dosing regimen can be 20 mg per kg bodyweight of a human patient administered on a bi-monthly or quarterlybasis for a period of at least 1 year (such as 2 or more years).

Off-drug periods i.e. periods in which the anti-sclerostin antibody isnot administered are also contemplated by the present invention,depending on the clinical requirements of the patient. Thus, in oneembodiment the treatment with the anti-sclerostin antibody isdiscontinued for one or more (such as 2, 3, 4, 5, 6, 8, 10, 12 or more)months or even one or more years.

Measurements of the targets are known in the art. For example, bonemineral density may be measured by dual-energy x-ray absorptiometry(DXA), single-energy x-ray absorptiometry (SXA), quantitative computedtomography (CT), and ultrasound. DXA is an x-ray technique that hasbecome the standard for measuring bone density in the art. Though it canbe used for measurements of any skeletal site, clinical determinationsare usually made of the lumbar spine and hip. Portable DXA machines havebeen developed that measure the heel (calcaneus), forearm (radius andulna), or finger (phalanges), and DXA can also be used to measure bodycomposition. Consequently, it has become standard practice to relate theresults to “normal” values using T-scores, which compare individualresults to those in a young population that is matched for race andgender. Alternatively, Z-scores compare individual results to those ofan age-matched population that is also matched for race and gender.Thus, for example, a 60-year-old woman with a Z-score of −1 (1 SD belowmean for age) could have a T-score of −2.5 (2.5 SD below mean for ayoung control group).

Yet another exemplary treatment regime entails administration ofmultiple doses, which may be of the same dosage or different dosagesranging from, e.g., about 5-20 mg/kg, for a long term use without aspecific timeline to stop the administration. This may be the treatmentregime to follow when a dose is needed to maintain an improved symptomin a continuous basis.

In other embodiments, dosage regimens for the anti-sclerostin antibodyinclude three doses at the same dosage, e.g., at 5 mg/kg body weight, 10mg/kg body weight, or 20 mg/kg body weight by intravenous administrationsequentially with an interval of 1-3 weeks, preferably 2 weeks betweentwo consecutive doses. In other embodiments, dosage regimens for theanti-sclerostin antibody include three doses at the three differentdosages, e.g., first at 5 mg/kg body weight, then 10 mg/kg body weight,and finally 20 mg/kg body weight by intravenous administrationsequentially with an interval of 1-3 weeks, preferably 2 weeks betweentwo consecutive doses. In still other embodiments, dosage regimens forthe anti-sclerostin antibody include three doses at the three differentdosages, e.g., first at 20 mg/kg body weight, then 10 mg/kg body weight,and finally 5 mg/kg body weight by intravenous administrationsequentially with an interval of 1-3 weeks, preferably 2 weeks betweentwo consecutive doses.

In some embodiments, the anti-sclerostin antibody of the invention andone or more monoclonal antibodies with different binding specificitiesare administered simultaneously or sequentially, in which case thedosage of each antibody administered falls within the ranges indicated.In one embodiment the one or more additional monoclonal antibodies arealso anti-sclerostin antibodies. Antibody is usually administered onmultiple occasions. Intervals between single dosages can be, forexample, weekly, monthly, every two months (i.e. bi-monthly) every threemonths (i.e. quarterly) or yearly. Intervals can also be irregular asindicated by measuring blood levels of antibody to the target antigen inthe patient. In some methods, dosage is adjusted to achieve a plasmaantibody concentration of about 1-1000 μg/ml and in some methods about25-300 μg/ml. In one embodiment, dosage of anti-sclerostin antibody ofthe invention is adjusted to achieve a plasma antibody concentration ofabout 1-1000 μg/ml or about 25-300 μg/ml.

Alternatively, in some embodiments, the anti-sclerostin antibody of theinvention can be administered to OI patients as a sustained releaseformulation, in which case less frequent administration is required.Dosage and frequency vary depending on the half-life of the antibody inthe patient. In general, human antibodies show the longest half-life,followed by humanized antibodies, chimeric antibodies, and nonhumanantibodies. The dosage and frequency of administration can varydepending on whether the treatment is prophylactic or therapeutic. Inprophylactic applications, a relatively low dosage is administered atrelatively infrequent intervals over a long period of time. Somepatients continue to receive treatment for the rest of their lives. Intherapeutic applications, a relatively high dosage at relatively shortintervals is sometimes required until progression of the disease isreduced or terminated or until the patient shows partial or completeamelioration of symptoms of disease. Thereafter, the patient can beadministered a prophylactic regime.

In some embodiments, actual dosage levels of the anti-sclerostinantibody may be varied so as to obtain an amount of the anti-sclerostinantibody which is effective to achieve the desired therapeutic responsefor a particular OI patient, composition, and mode of administration,without being toxic to the patient. The selected dosage level willdepend upon a variety of pharmacokinetic factors including the activityof the particular compositions of the present invention employed, theroute of administration, the time of administration, the rate ofexcretion of the particular anti-sclerostin antibody being employed, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular compositions employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.

A “therapeutically effective amount” of the anti-sclerostin antibody mayresult in a decrease in severity of disease symptoms, an increase infrequency and duration of disease symptom-free periods, or a preventionof impairment or disability due to the disease affliction.

A composition of the anti-sclerostin antibody can be administeredintravenously using one or more of a variety of methods known in theart. Administration for antibodies of the invention occurs via theintravenous route. In one embodiment, administration occursintravenously by way of an infusion.

The anti-sclerostin antibody can be prepared with carriers that mayprotect the compound against rapid release, such as a controlled releaseformulation. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Many methods for the preparationof such formulations are patented or generally known to those skilled inthe art. See, e.g., Sustained and Controlled Release Drug DeliverySystems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

Patient Group

In one embodiment, the methods and uses described herein are fortreating osteogenesis imperfecta using anti-sclerostin antibodiesdescribed herein. OI is classified by the genetics and severity ofdisease, and can be classified as type I OI, type II OI, type III OI,type IV OI, or type V OI according to the classification of Van Dijk andSillence (2014, Am J Med Genet Part A 164A:1470-1481 and Van Dijk andSillence, 2014, Am J Med Genet Part A 167A:1178; which are incorporatedin their entirety by reference thereto). Classification relies on acombination of clinical evaluation/diagnosis, biochemical analysis aswell as molecular genetic testing, and is routine for those skilled inthe art. The OI nomenclature as used herein is as proposed by Van Dijkand Sillence, as referenced in the publications above.

In 80%-90% of people with OI, OI is caused by mutations in the COL1A1and COL1A2 genes (17q21.33 and 7q22.3, respectively) encoding the alpha1 and alpha 2 chains of type-I collagen. A comprehensive database ofover 1000 known mutations has been published along with agenotype-phenotype correlation (https://oi.gene.le.ac.uk/home.php;accessed 12 Dec. 2016). Mutations in other genes, such as CRTAP, LEPRE1or PPIB, are also known. Molecular genetic tests for mutations in i.a.the COL1A1 and COL1A2 genes are known and routine for those skilled inthe art. By way of example, Korkko et al. (1998) describe PCRamplification of the COL1A1 gene and the COL1A2 genes followed bymutation scanning by conformation-sensitive gel electrophoresis (CSGE)(Am. J. Hum. Genet. 62:98-110, 1998). van Dijk et al. (2010) describeCOL1A1 mutation detection by a multiplex ligation-dependent probeamplification (MLPA) technique (Genet Med 12(11):736-741). Morerecently, Árvai, K. et al. (2016) describe next-generation sequencingmethods (Sci. Rep. 6, 28417). These references are hereby incorporatedby reference thereto.

In one embodiment, the methods and uses described herein are fortreating patients who exhibit a deficiency of type-I collagen, e.g. 01types I-IV. As a result, the normal architecture of bone, consisting ofcollagen fibrils and hydroxyapatite crystals, is altered and causesbrittleness. In one embodiment, the methods and uses herein are fortreating human OI patients characterized by one or more mutations inCOL1A1 and/or COL1A2.

In one embodiment, the methods and uses described herein are fortreating OI type I, III and/or IV. In one embodiment, OI type I, III andIV are confirmed by DNA testing i.e. detection of COL1A1/COL1A2mutations. Thus, in one embodiment the methods and uses herein are fortreating OI type I, III and/or IV characterized by one or more mutationsin COL1A1 and/or COL1A2.

In some embodiments, the methods and uses of the anti-sclerostinantibody of the invention are for treating a mild to moderate form ofOI. In other embodiments of the methods and uses of the anti-sclerostinantibody, the patient under treatment has a type I OI, a type II 01, atype III 01, or a type IV OI. In still other embodiments of the methodsand uses of the anti-sclerostin antibody, the OI patients are adultpatients aged 18 and above. In yet still other embodiments of themethods and uses of the anti-sclerostin antibody, the OI patients arepediatric patients. Pediatric patients as defined herein embraceschildren aged 0-17 such as those aged 2-17, 3-17, 4-17 or 5-17. The termpatients, as used herein, means human patients.

Pharmaceutical Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition for increasing bone formation and reducing bone resorptionin a patient suffering from osteogenesis imperfecta, which compositioncontains the anti-sclerostin antibody as described above. Thepharmaceutical composition may be formulated with a pharmaceuticallyacceptable carrier. In one aspect, the invention provides apharmaceutical composition comprising an anti-sclerostin antibody asdisclosed herein. In one embodiment, the pharmaceutical compositioncomprising the anti-sclerostin antibody is for use in treating OI.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. The carrier should be suitable forintravenous, intramuscular, subcutaneous, parenteral, spinal orepidermal administration (e.g., by injection or infusion). Depending onthe route of administration, the anti-sclerostin antibody, may be coatedin a material to protect the compound from the action of acids and othernatural conditions that may inactivate the compound.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofpresence of microorganisms may be ensured both by sterilizationprocedures, and by the inclusion of various antibacterial and antifungalagents, for example, paraben, chlorobutanol, phenol sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like into the compositions. Inaddition, prolonged absorption of the injectable pharmaceutical form maybe brought about by the inclusion of agents which delay absorption suchas, aluminum monostearate and gelatin.

Pharmaceutically acceptable carriers include sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersion. The use of such media andagents for pharmaceutically active substances is known in the art.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the pharmaceutical compositions ofthe invention is contemplated. Supplementary active compounds can alsobe incorporated into the compositions.

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed bysterilization microfiltration. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the methods of preparation are vacuumdrying and freeze-drying (lyophilization) that yield a powder of theactive ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof. Thus, in one embodiment,the anti-sclerostin antibody of the invention/pharmaceutical compositionof the invention is formulated as a lyophilizate powder. In a relatedembodiment, the lyophilizate is reconstituted prior to administration.Suitable liquids for reconstitution include water for injection (wfi).

The amount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thesubject being treated, and the particular mode of administration. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will generally be that amountof the composition which produces a therapeutic effect. Generally, outof one hundred percent, this amount will range from about 0.01 percentto about ninety-nine percent of active ingredient, from about 0.1percent to about 70 percent, or from about 1 percent to about 30 percentof active ingredient in combination with a pharmaceutically acceptablecarrier.

Pharmaceutical compositions of the invention and antibodies of theinvention may also be administered in a combination therapy, i.e.,combined with other active agents. For example, the combination therapycan include an anti-sclerostin antibody of the present inventioncombined with at least one other anti-inflammatory or anti-osteoporoticagent. Examples of therapeutic agents that can be used in combinationtherapy include bisphosphonates (such as alendronate, risedronatesodium, ibandronic acid, zoledronic acid, olpadronate, neridronate,skelid, bonefos), parathyroid hormone (e.g. teriparatide (rdna origin)injection), calcilytics, calcimimetics (e.g., cinacalcet), statins,anabolic steroids, lanthanum and strontium salts, and sodium fluoride.Thus, in one embodiment the anti-sclerostin antibodies of the inventioncan be administered in combination with one or more agents selectedfrom: a calcitonin or an analogue or derivative thereof, e.g. salmon,eel or human calcitonin, calcilytics, calcimimetics (e.g., cinacalcet),a steroid hormone, e.g. an estrogen, a partial estrogen agonist orestrogen-gestagen combination, a SERM (Selective Estrogen ReceptorModulator) e.g. raloxifene, lasofoxifene, bazedoxifene, arzoxifene,FC1271, Tibolone (Livial®), a SARNI (Selective Androgen ReceptorModulator), a RANKL antibody (such as denosumab), a cathepsin Kinhibitor, vitamin D or an analogue thereof or PTH, a PTH fragment or aPTH derivative e.g. PTH (1-84) (such as Preos™ (parathyroid hormone1-84)), PTH (1-34) (such as Forteo™ (teriparatide (rdna origin)injection)), PTH (1-36), PTH (1-38), PTH (1-31)NH2 or PTS 893. Accordingto another embodiment, the antibodies of the invention may be employedin combination with other current osteoporosis therapy approaches,including bisphosphonates (e.g., Fosamax™ (alendronate), Actonel™(risedronate sodium), Bonviva™ (ibandronic acid), Zometa™ (zoledronicacid), Aclasta™/Reclast™ (zoledronic acid), olpadronate, neridronate,skelid, bonefos), statins, anabolic steroids, lanthanum and strontiumsalts, and sodium fluoride.

In one embodiment, the antibodies of the invention may be administeredin combination with an LRP4 modulating agent, i.e., an agent modulatingthe expression or activity of LRP4, e.g, an LRP4 neutralizing antibody.

In one embodiment, the antibodies of the invention may be administeredin combination with an LRP5 modulating agent, i.e., an agent modulatingthe expression or activity of LRP5, e.g, an LRP5 neutralizing antibody.

In another embodiment, the antibodies of the invention may beadministered in combination with a DKK1 modulating agent, i.e., an agentthat interfere or neutralize Dkk-1 mediated antagonism of Wnt signaling,e.g., a DKK1 neutralizing antibody.

In one embodiment, the antibodies of the invention may be administeredin combination with a bisphosphonate e.g. alendronate, risedronatesodium, ibandronic acid, zoledronic acid, zoledronic acid, olpadronate,neridronate, skelid, bonefos.

In one embodiment, the antibodies of the invention may be administeredin combination with (i) zoledronic acid, (ii) an anti-DKK1 antibody,(iii) alendronate, (iv) an anti-LRP4 antibody, (v) hPTH and/or (vi)parathyroid hormone releasing agents (calcilytics).

Other agents which can be administered in combination with theanti-sclerostin antibodies of the invention include vitamin D and/orcalcium. In one embodiment the vitamin D and/or calcium is administeredif the patient has a vitamin D and/or calcium deficiency.

In one embodiment, the antibodies of the invention are administeredtogether with another agent (e.g. the above mentioned agents), in asequential manner (i.e. one after the other) or simultaneously. In oneembodiment, the anti-sclerostin antibody is administered according tothe aforementioned doses and frequencies of administration. Suitabledoses for the combination therapy agent can be varied according to theclinical requirements of the patient.

The compositions are preferably formulated at physiological pH.

Therapeutic compositions can be administered with medical devices knownin the art. For example, in one embodiment, a therapeutic composition ofthe invention can be administered with a needleless hypodermic injectiondevice, such as the devices shown in U.S. Pat. Nos. 5,399,163;5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.Examples of well-known implants and modules useful in the presentinvention include: U.S. Pat. No. 4,487,603, which shows an implantablemicro-infusion pump for dispensing medication at a controlled rate; U.S.Pat. No. 4,486,194, which shows a therapeutic device for administeringmedicaments through the skin; U.S. Pat. No. 4,447,233, which shows amedication infusion pump for delivering medication at a precise infusionrate; U.S. Pat. No. 4,447,224, which shows a variable flow implantableinfusion apparatus for continuous drug delivery; U.S. Pat. No.4,439,196, which shows an osmotic drug delivery system havingmulti-chamber compartments; and U.S. Pat. No. 4,475,196, which shows anosmotic drug delivery system. These patents are incorporated herein byreference. Many other such implants, delivery systems, and modules areknown to those skilled in the art. In one embodiment, the therapeuticcomposition of the invention can be administered with a syringe.

In certain embodiments, the antibodies of the invention can beformulated to ensure proper distribution in vivo.

In one aspect the invention provides use of an anti-sclerostin antibodyfor the manufacture of a medicament for the treatment of osteogenesisimperfecta. All of the other aspects/embodiments described herein applyequally to this particular aspect of the invention.

In another aspect the invention provides an anti-sclerostin antibody foruse in the treatment of osteogenesis imperfecta. All of the otheraspects/embodiments described herein apply equally to this particularaspect of the invention.

In one aspect, the invention provides an anti-sclerostin antibody foruse in a clinical trial for osteogenesis imperfecta comprising comparingthe number of fractures that have occurred in the clinical trialpopulation at an interim time point during the clinical trial periodwith the number of fractures expected at said interim time point forsaid clinical trial population.

In a related aspect, the invention provides a method of conducting aclinical trial for osteogenesis imperfecta with an anti-sclerostinantibody comprising comparing the number of fractures that have occurredin a clinical trial population at an interim time point during theclinical trial period with the number of fractures expected at saidinterim time point for said clinical trial population. In one embodimentof the aforementioned aspects, the aspect may further compriserecruiting additional patients to the clinical trial population if thenumber of fractures in the clinical trial population at the interim timepoint is lower than the expected number of fractures for said clinicaltrial population. In one embodiment, the clinical trial period isextended if the number of fractures in the clinical trial population atthe interim time point is lower than the expected number of fracturesfor said clinical trial population. In another embodiment, the clinicaltrial period is shortened if the number of fractures in the clinicaltrial population at the interim time point is higher than the expectednumber of fractures for said clinical trial population. The clinicaltrial population is made up of patients receiving the anti-sclerostinantibody and a control group of patients receiving a placebo. Anadvantage of these aspects/embodiments is that it allows the clinicaltrial period to be varied in response to developments in the clinic,which ultimately leads to a more efficient and cost-effective clinicaltrial which also benefits the patients. The expected number of fracturescan be calculated from a baseline fracture rate which can be derivedfrom historical data and/or from data from the clinical trial populationprior to commencement of the clinical trial period. In one embodiment,the anti-sclerostin antibody is an anti-sclerostin antibody as definedherein. The interim time point can be varied and selected according towhen a statistically significant comparison can be made. The clinicaltrial period begins with the administration of the anti-sclerostinantibody or placebo and ends once the final dose of anti-sclerostinantibody/placebo has been administered and the relevant data collected.

Sequence of BPS804 H-chain (SEQ ID NO: 172):QVQLVESGGGLVQPGGSLRLSCAASGFTFRSHWLSWVRQAPGKGLEWVSNINYDGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDTYLHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTEPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFELYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSequence of BPS804 L-chain (SEQ ID NO: 173):DIALTQPASVSGSPGQSITISCTGTSSDVGDINDVSWYQQHPGKAPKLMIYDVNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCQSYAGSYLSEVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQV THEGSTVEKTVAPTECS

MODES FOR CARRYING OUT THE INVENTION Example 1

This example describes a clinical trial to assess the use of ananti-sclerostin antibody in the treatment of adult patients with OI. Thepatients were treated with three sequential intra-patient escalatingdoses of anti-sclerostin antibody BPS804, given as intravenous infusionsseparated by 2 weeks from each dose. An untreated reference group wasenrolled as well for monitoring and observation of the natural OIdisease progression with regard to changes in bone biomarker profiles.This trial was a randomized, open-label, intra-patient dose escalatingstudy with an untreated reference group in 14 adult patients withmoderate OI. Patients were randomized to the treatment group or thereference group at a ratio of 2:1.

Patients were administered every two weeks with escalating doses of theanti-sclerostin antibody: Week 1: 5 mg/kg, Week 3: 10 mg/kg and Week 5:20 mg/kg. The treatment period was followed by an about 3.6 monthfollow-up period. Patients who were randomized to the untreatedreference group at screening were only admitted to the study site atweek 7, study Day 43 and at the end of the study.

A description of the study drug BPS804 is presented in Table 1. BPS804solution for infusion was administered as an infusion at a flow rate ofabout 2 mL/min until the desired dose has been delivered.

Biomarkers of bone metabolism including procollagen I N-terminalpropeptide (PINP), procollagen I C-terminal propeptide (PICP),bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and bonemineral density (BMD) (measured by DXA) were assayed at baseline, day 43and day 141.

TABLE 1 Study Drug BPS804 Name BPS804 Formulation Powder for solutionfor infusion (lyophilizate in vial) Appearance before White lyophilizatecake reconstitution Appearance after Opalescent to clear, colorlesssolution reconstitution Unit dose 150 mg per vial * Packaging 6 mL TypeI glass vials Diluent for iv Dextrose 5% in water (USP or equivalent) in250 administration mL * The vials contain a 20% overfill to allow acomplete withdrawal of the labeled amount of BPS804.

Of the 14 patients enrolled in the study, nine patients were exposed toanti-sclerostin antibody treatment. The overall mean age of the patientswas marginally higher in the anti-sclerostin antibody group (30.7 years)when compared to the reference group (27.4 years). The overall meanweight and height between the two groups were very similar. Summary ofpatient demographics is presented in Table 2. The overall median scoresof the lumbar spine z-score were comparatively lower in theanti-sclerostin antibody group. The overall years on bisphosphonatescannot be compared between the groups considering the relative size ofthe number of the patients in each group. See Table 3.

TABLE 2 Demographic Summary By Treatment Group BPS804 Reference Total N= 9 N = 5 N = 14 Age (years) Mean (SD) 30.7 (13.47) 27.4 (15.47) 29.5(13.71) Median  25.0  21.0  21.5 Range 19, 57 19, 55 19, 57 Sex - n (%)Male 7 (77.8) 3 (60.0) 10 (71.4) Female 2 (22.2) 2 (40.0) 4 (28.6)Predominant Race - n (%) Caucasian 9 (100) 5 (100) 14 (100) Ethnicity -n (%) Mixed ethnicity 1 (11.1) 1 (20.0) 2 (14.3) Other 8 (88.9) 4 (80.0)12 (85.7) Weight (kg)* Mean (SD) 61.84 (14.378) 58.20 (13.034) 60.54(13.519) Median  63.90  54.00  59.45 Range 43.5, 80.1 44.0, 75.0 43.5,80.1 Height (cm)* Mean (SD) 161.6 (12.19) 162.8 (13.85) 162.0 (12.28)Median 162.0 161.0 162.0 Range 142, 178 142, 176 142, 178 *Weight andheight are taken from Screening vital signs evaluations.

TABLE 3 Disease Characteristics By Treatment Group At Study Entry BPS804Reference Total N = 9 N = 5 N = 14 Lumbar spine z-score* Mean (SD) −2.59(1.191) −2.18 (0.514) −2.44 (0.997) Median −2.30 −2.07 −2.19 Range −4.9,−1.1 −2.9, −1.5 −4.9, −1.1 Yrs. on bisphosphonates# N 2   1   3   Mean(SD) 8.53 (4.882) 15.46 (—) 10.84 (5.283) Median  8.53 15.46 11.99 Range5.1, 12.0 15.5, 15.5 5.1, 15.5 Subjects with D43 9 (100) 5 (100) 14(100) Biomarker data - n (%) Subjects with D141 9 (100) 4 (80.0) 13(92.9) BMD data - n (%) *Lumbar spine z-score is taken at screening.#Years on bisphosphonates is calculated from the medical history page,by taking the difference between the earliest start date ofbisphosphonates medication and date of screening.

The assay results of the bone metabolism biomarkers for the study arepresented in FIG. 1. The ratios of geometric means for PINP, PICP, BSAP,and OC at Day 43 were 1.84, 1.53, 1.59 and 1.44 with P-values of <0.001,0.003, <0.001, and 0.012 in the BPS804 group. The ratio of geometricmeans for BMD at Day 141 was 1.04 with P-value of 0.038.

The Bayesian analysis of change from baseline for PINP, PICP, and BSAPshowed a posterior probability of around 90% or higher for an increaseof at least 70% (PINP) or 30% (PICP, BSAP). The Bayesian analysis forBMD showed a posterior probably of 98% for an increase in BMD, and 87%for an increase of at least 2%. See FIG. 3, FIG. 4, FIG. 5, FIG. 6 andFIG. 7 for details on the PINP, PICP, B SAP, OC and BMD results,respectively.

The geometric mean results on CTX-1 from Day 8 through Day 43 showed adecrease in CTX-1 concentration levels which together with boneformation biomarker results supports bone anabolic effects. FIG. 8presents the details of the values since Baseline. On Day 43, the ratiofrom baseline in the BPS804 group was 56% of baseline, thus a reductionby 44%. The concentration levels steadily increased from Day 50 throughDay 85 with a marginal decrease on Days 113 and 141.

The comparison of ratios with the matching ratios in the reference groupwere performed as per the planned two sample t-tests (1-sided) and aP-value of below 0.1 in this comparison was considered supportiveevidence for efficacy. Based on the two sample t-tests analysis, theP-values were <0.001, 0.014, 0.006, and 0.015 for PINP, PICP, BSAP, andOC, respectively, which supported the evidence for efficacy. The p-valuefor treatment group comparison of BMD was 0.1, also supporting theevidence that increase was larger under the anti-sclerostin antibodythan in the reference group. See FIG. 2. These analyses confirmed theevidence of higher increase in the anti-sclerostin antibody group thanin the reference group, for all three biomarker data and for the BMDdata.

After administration of the anti-sclerostin antibody, median PINP, PICP,BSAP activity, and OC levels were increased at Day 43 by 84%, 53%, 59%,and 44%, respectively, while corresponding biomarkers remained unchangedor declined moderately in the untreated reference group. Further, afteradministration of the anti-sclerostin antibody, CTX-1 level wasdecreased by 44% at Day 43 from baseline. The increase of bone formationbiomarker (PINP, PICP, BSAP and OC) levels and the reduction of boneresorption biomarker (CTX-1) level were in line with the observedincrease by ˜4% in lumbar spine BMD at Day 141 in the anti-sclerostinantibody treatment group, thus confirming the first clinical evidence ofbone anabolic effects of an anti-sclerostin antibody in patients withosteogenesis imperfecta.

In addition, the study showed that the anti-sclerostin antibody was safeand well-tolerated in the adult patients with OI. The most commonlyreported AEs were headache, influenza, arthralgia, and fatigue. None ofthe reported AEs were considered related to the study drug. There wasone SAE (Goiter) of mild intensity reported in one patient in thereference group. This AE was considered serious because ofhospitalization. The SAE resolved prior to end-of-study. The AEs gave noindication of target organ toxicity. Three fractures were reportedduring the study (subject 5103—Day 47, subject 5109—Day 4, Subject5113—Day 4). There were also no clinically significant abnormalities ofhematological, clinical chemistry, urinalysis, ECG or vital sign datacompromising the patients' safety.

According to the clinical study results, with an osteoanabolic treatmentlike BPS804, bone formation or bone anabolic activity can be stimulatedin patients with OI. The increase in BMD results in improved bonequality thereby leading to a reduction in the fracture rate and risk.Genotyping might be warranted to identify or predict OI patients whomight benefit most from such a treatment strategy.

Example 2

A pharmacokinetic (PK) model was developed for BPS804 along with apharmacokinetic (PK) and pharmacodynamics (PD) (PK-PD) model forcirculating sclerostin effects after BPS804 administration based on acombination of clinical trial data and publically available data onother anti-sclerostin antibodies. The PK-PD model was linked to anexisting systems pharmacology model to evaluate proposed dosing regimensfor BPS804. Model simulations were used to provide guidance for doseselection and dosing interval over 1-2 years of treatment for typical OIpatients. These included scenarios with different dosing considerationsfor the first year (e.g., comparison of dosage amount and QM (i.e.monthly) vs. Q3M (i.e. quarterly) dosing) as well as considerations forsubsequent years (e.g., switching from QM to Q3M dosing).

Results:

The data demonstrated that BPS804 dosing regimens nearing maximal (>75%)inhibition of sclerostin provide near maximal responses in circulatingsclerostin, bone turnover markers (BTM), and lumbar spine bone mineraldensity (BMD). To demonstrate this, a range of doses from 0.1 mg/kg to20 mg/kg were simulated using QM (i.e. monthly) and Q3M (i.e. quarterly)intervals for a two-year time-course. Results were evaluated assumingfull BPS804 exposure effects on sclerostin and relative to maximalinhibition. Overall, the 20 mg/kg QM dose approached the maximalsclerostin response. The maximum level of inhibition was reached by bothmonthly and quarterly dosing regimens, alike, and both the QM and Q3M 20mg/kg dosing regimens reached the maximum inhibition level.

The modeling results further indicated that a BPS804 20 mg/kg QM dosewould provide similar or a slightly greater 12-month BMD increasecompared with Q3M dosing due to the longer sustained inhibition ofsclerostin with BPS804.

Following one-year of treatment with BPS804 20 mg/kg QM, nearly the samepeak maximum sclerostin response can also achieved with a 20 mg/kg doseadministered quarterly. This potential change in dosing regimen afterone-year of dosing could reflect the attainment of an apparent newsteady-state in the bone remodeling system after one year of sclerostininhibition therapy. Therefore, less frequent dosing after the first yearof dosing may allow for maintenance of BMD increases from the first yearof dosing.

In summary, the modelling data show that BPS804 20 mg/kg QM dosing isexpected to provide near maximal inhibition of sclerostin that wouldtranslate into maximal BMD response. In addition, extending dosingintervals for longer-term dosing (e.g., switching to dosing every twomonths (Q2M) or Q3M following one-year of QM dosing) may be advantageousgiven the observed changes in bone turnover markers following the firstyear of treatment.

The patents and publications listed herein describe the general skill inthe art. In the case of any conflict between a cited reference and thisspecification, the specification shall control. In describingembodiments of the present application, specific terminology is employedfor the sake of clarity. However, the invention is not intended to belimited to the specific terminology so selected. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. All examples presented are representative and non-limiting.The above-described embodiments may be modified or varied, withoutdeparting from the invention, as appreciated by those skilled in the artin light of the above teachings. It is therefore to be understood that,within the scope of the claims and their equivalents, the invention maybe practiced otherwise than as specifically described.

1. A method for treating osteogenesis imperfecta (OI) in a human patientcomprising administering to the human patient a therapeuticallyeffective amount of an anti-sclerostin antibody, wherein theanti-sclerostin antibody comprises: (a) a heavy chain variable regionCDR1 comprising an amino acid sequence set forth in SEQ ID NO:4; (b) aheavy chain variable region CDR2 comprising an amino acid sequence setforth in SEQ ID NO:15; (c) a heavy chain variable region CDR3 comprisingan amino acid sequence set forth in SEQ ID NO:26; (d) a light chainvariable region CDR1 comprising an amino acid sequence set forth in SEQID NO:37; (e) a light chain variable region CDR2 comprising an aminoacid sequence set forth in SEQ ID NO:48; and (f) a light chain variableregion CDR3 comprising an amino acid sequence set forth in SEQ ID NO:59;and wherein the anti-sclerostin antibody is administered intravenouslyat a dose of 1-50 mg per kg body weight of the human patient.
 2. Themethod according to claim 1, wherein the OI is type I OI, type III OI ortype IV OI.
 3. The method according to claim 1 or claim 2, wherein thehuman patient has one or more mutations in the COL1A1 and/or COL1A2genes.
 4. The method according to any one of claims 1-3, wherein theanti-sclerostin antibody comprises: a) a VH polypeptide sequence havingat least 90 percent sequence identity to the amino acid sequences setforth as SEQ ID NO:70; and/or b) a VL polypeptide sequence having atleast 90 percent sequence identity to the amino acid sequences set forthas SEQ ID NO:81.
 5. The method according to claims 1-4, wherein theanti-sclerostin antibody comprises a VL polypeptide sequence comprisingthe amino acid sequence set forth as SEQ ID NO:81 and a VH polypeptidesequence comprising the amino acid sequence set forth as SEQ ID NO:70.6. The method according to any one of claims 1-5, wherein theanti-sclerostin antibody comprises: a) a full length heavy chain aminoacid sequence having at least 90 percent sequence identity to the aminoacid sequence set forth as SEQ ID NO:172; and/or b) a full length lightchain amino acid sequence having at least 90 percent sequence identityto the amino acid sequence set forth as SEQ ID NO:173.
 7. The methodaccording to any one of claims 1-6, wherein the anti-sclerostin antibodycomprises a full length light chain amino acid sequence comprising theamino acid sequence set forth as SEQ ID NO: 173 and a full length heavychain amino acid sequence comprising the amino acid sequence set forthas SEQ ID NO:
 172. 8. The method according to any preceding claim,wherein the anti-sclerostin antibody is administered at a dose of 10-30mg per kg body weight of the human patient.
 9. The method according toany preceding claim, wherein the anti-sclerostin antibody isadministered to the human patient on a daily, weekly, bi-weekly,monthly, bi-monthly or quarterly basis.
 10. The method according to anypreceding claim, wherein the anti-sclerostin antibody is administered tothe human patient on a monthly basis.
 11. The method according to anypreceding claim, wherein the anti-sclerostin antibody is administered tothe human patient on a bi-monthly or quarterly basis.
 12. The methodaccording to any preceding claim, wherein the treatment regimencomprises a first dosing regimen optionally followed by a second dosingregimen.
 13. The method according to claim 12 wherein the first dosingregimen is 1-50 mg per kg body weight of a patient administered on amonthly basis.
 14. The method according to claim 12, wherein the firstdosing regimen is 20 mg per kg body weight of a patient administered ona monthly basis.
 15. The method according to any one of claims 12-14,wherein the second dosing regimen is 1-50 mg per kg body weight of apatient administered on a bi-monthly or quarterly basis.
 16. The methodaccording to any one of claims 12-15, wherein the second dosing regimenis 20 mg per kg body weight of a patient administered on a bi-monthly orquarterly basis.
 17. The method according to any one of claims 12-16,wherein the first dosing regimen is 20 mg per kg body weight of apatient administered on a monthly basis and the second dosing regimen is20 mg per kg body weight of a patient administered on a bi-monthly orquarterly basis.
 18. The method according to claim 17, wherein the firstdosing regimen is 20 mg per kg body weight of a patient administered ona monthly basis for a period of 1 year, and the second dosing regimen is20 mg per kg body weight of a patient administered on a bi-monthly orquarterly basis for a period of at least 1 year.
 19. The methodaccording to any preceding claim, comprising administering a furthertherapeutic agent, such as bisphosphonate, parathyroid hormone,calcilytics, calcimimetics (e.g., cinacalcet), statins, anabolicsteroids, lanthanum and strontium salts, and/or sodium fluoride.
 20. Alyophilizate comprising an anti-sclerostin antibody as defined in anyone of claims 1-7.
 21. The lyophilizate according to claim 20, furthercomprising sucrose, arginine hydrochloride, L-histidine, polysorbate 80,and hydrochloric acid.
 22. A kit comprising an anti-sclerostin antibodyas defined in any one of claims 1-7, or a lyophilizate according toclaim 20 or claim 21
 23. The kit according to claim 22 comprising afurther therapeutic agent, such as a combination therapy agent e.gbisphosphonate, parathyroid hormone, calcilytics, calcimimetics (e.g.,cinacalcet), statins, anabolic steroids, lanthanum and strontium salts,and/or sodium fluoride.
 24. The anti-sclerostin antibody as defined inany one of claims 1-7, the lyophilizate according to claim 20 or claim21, or the kit according to claim 22 or claim 23, for use in a methodaccording to any one of claims 1-19.
 25. The method, anti-sclerostinantibody, lyophilizate, kit, and/or use substantially as describedherein with reference to the drawings.